tbuckley/cabot-search huggingface dataset:
Long-Term Stability of Coverage Among Michigan Medicaid Beneficiaries
Authors: Chima D. Ndumele, Anthony Lollo, Harlan M. Krumholz, Mark Schlesinger, Jacob Wallace
Journal: Annals of Internal Medicine (2022)

Medicaid, the primary source of insurance coverage for disadvantaged Americans, was originally designed as a temporary safety-net program. No studies have used long-run data to assess the recent use of the program by beneficiaries.To assess patterns of short- and long-term enrollment among beneficiaries, using a 10-year longitudinal panel of Michigan Medicaid eligibility data.Primary analyses assessing trends in Medicaid enrollment among cohorts of existing and new beneficiaries.Administrative records from Michigan Medicaid for the period 2011 to 2020.3.97 million Medicaid beneficiaries.Short- and long-term enrollment in the program.The sample includes 3.97 million unique beneficiaries enrolled at some point between 2011 and 2020. Among a cohort of 1.23 million beneficiaries enrolled in 2011, over half (53%) were also enrolled in Medicaid in June 2020, spending, on average, two-thirds of that period (67%) on Medicaid. These beneficiaries, however, experienced substantial lapses in coverage, as only 25% were continuously enrolled throughout the period. Enrollment was less stable when assessed from the perspective of newly enrolled beneficiaries, of whom only 37% remained enrolled at the end of the study period.Primary estimates from a single state.For many beneficiaries, Medicaid has served as their primary source of coverage for at least a decade. This pattern would justify increasing investments in the program to improve long-term health outcomes.Self-funded.
GPC2 antibody–drug conjugate reprograms the neuroblastoma immune milieu to enhance macrophage-driven therapies
Authors: Guillem Pascual-Pasto, Brendan McIntyre, Rawan Shraim, Samantha N Buongervino, Amy K Erbe, Doncho V Zhelev, Shakhnozakhon Sadirova, Anna M Giudice, Daniel Martinez, Laura Garcia-Gerique, Dimiter S Dimitrov, Paul M Sondel, Kristopher R Bosse
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Antibody–drug conjugates (ADCs) that deliver cytotoxic drugs to tumor cells have emerged as an effective and safe anticancer therapy. ADCs may induce immunogenic cell death (ICD) to promote additional endogenous antitumor immune responses. Here, we characterized the immunomodulatory properties of D3-GPC2-PBD, a pyrrolobenzodiazepine (PBD) dimer-bearing ADC that targets glypican 2 (GPC2), a cell surface oncoprotein highly differentially expressed in neuroblastoma. Methods ADC-mediated induction of ICD was studied in GPC2-expressing murine neuroblastomas in vitro and in vivo. ADC reprogramming of the neuroblastoma tumor microenvironment was profiled by RNA sequencing, cytokine arrays, cytometry by time of flight and flow cytometry. ADC efficacy was tested in combination with macrophage-driven immunoregulators in neuroblastoma syngeneic allografts and human patient-derived xenografts. Results The D3-GPC2-PBD ADC induced biomarkers of ICD, including neuroblastoma cell membrane translocation of calreticulin and heat shock proteins (HSP70/90) and release of high-mobility group box 1 and ATP. Vaccination of immunocompetent mice with ADC-treated murine neuroblastoma cells promoted T cell-mediated immune responses that protected animals against tumor rechallenge. ADC treatment also reprogrammed the tumor immune microenvironment to a proinflammatory state in these syngeneic neuroblastoma models, with increased tumor trafficking of activated macrophages and T cells. In turn, macrophage or T-cell inhibition impaired ADC efficacy in vivo, which was alternatively enhanced by both CD40 agonist and CD47 antagonist antibodies. In human neuroblastomas, the D3-GPC2-PBD ADC also induced ICD and promoted tumor phagocytosis by macrophages, which was further enhanced when blocking CD47 signaling in vitro and in vivo. Conclusions We elucidated the immunoregulatory properties of a GPC2-targeted ADC and showed robust efficacy of combination immunotherapies in diverse neuroblastoma preclinical models.
Ecology, Not Host Phylogeny, Shapes the Oral Microbiome in Closely Related Species
Authors: Markella Moraitou, Adrian Forsythe, James A Fellows Yates, Jaelle C Brealey, Christina Warinner, Katerina Guschanski
Journal: Molecular Biology and Evolution (2022)

Host-associated microbiomes are essential for a multitude of biological processes. Placed at the contact zone between external and internal environments, the little-studied oral microbiome has important roles in host physiology and health. Here, we investigate the roles of host evolutionary relationships and ecology in shaping the oral microbiome in three closely related gorilla subspecies (mountain, Grauer's, and western lowland gorillas) using shotgun metagenomics of 46 museum-preserved dental calculus samples. We find that the oral microbiomes of mountain gorillas are functionally and taxonomically distinct from the other two subspecies, despite close evolutionary relationships and geographic proximity with Grauer's gorillas. Grauer's gorillas show intermediate bacterial taxonomic and functional, and dietary profiles. Altitudinal differences in gorilla subspecies ranges appear to explain these patterns, suggesting a close connection between dental calculus microbiomes and the environment, likely mediated through diet. This is further supported by the presence of gorilla subspecies-specific phyllosphere/rhizosphere taxa in the oral microbiome. Mountain gorillas show a high abundance of nitrate-reducing oral taxa, which may promote adaptation to a high-altitude lifestyle by modulating blood pressure. Our results suggest that ecology, rather than evolutionary relationships and geographic distribution, shape the oral microbiome in these closely related species.
Genetic Drift Shapes the Evolution of a Highly Dynamic Metapopulation
Authors: Pascal Angst, Camille Ameline, Christoph R Haag, Frida Ben-Ami, Dieter Ebert, Peter D Fields
Journal: Molecular Biology and Evolution (2022)

The dynamics of extinction and (re)colonization in habitat patches are characterizing features of dynamic metapopulations, causing them to evolve differently than large, stable populations. The propagule model, which assumes genetic bottlenecks during colonization, posits that newly founded subpopulations have low genetic diversity and are genetically highly differentiated from each other. Immigration may then increase diversity and decrease differentiation between subpopulations. Thus, older and/or less isolated subpopulations are expected to have higher genetic diversity and less genetic differentiation. We tested this theory using whole-genome pool-sequencing to characterize nucleotide diversity and differentiation in 60 subpopulations of a natural metapopulation of the cyclical parthenogen Daphnia magna. For comparison, we characterized diversity in a single, large, and stable D. magna population. We found reduced (synonymous) genomic diversity, a proxy for effective population size, weak purifying selection, and low rates of adaptive evolution in the metapopulation compared with the large, stable population. These differences suggest that genetic bottlenecks during colonization reduce effective population sizes, which leads to strong genetic drift and reduced selection efficacy in the metapopulation. Consistent with the propagule model, we found lower diversity and increased differentiation in younger and also in more isolated subpopulations. Our study sheds light on the genomic consequences of extinction-(re)colonization dynamics to an unprecedented degree, giving strong support for the propagule model. We demonstrate that the metapopulation evolves differently from a large, stable population and that evolution is largely driven by genetic drift.
Developing current procedural terminology codes that describe the work performed by machines
Authors: Richard A. Frank, Robert Jarrin, Jordan Pritzker, Michael D. Abramoff, Michael X. Repka, Pat D. Baird, S. Marlene Grenon, Megan Ruth Mahoney, John E. Mattison, Ezequiel Silva
Journal: npj Digital Medicine (2022)

Abstract The “Taxonomy of Artificial Intelligence for Medical Services and Procedures” became part of the Current Procedural Terminology (CPT®) code set effective January 1, 2022. It provides a framework for discrete and differentiable CPT codes which; are consistent with the features of the devices’ output, characterize interaction between the device and the physician or other qualified health care professional, and foster appropriate payment. Descriptors include “Assistive”, “Augmentative”, and “Autonomous”. As software increasingly augments the provision of medical services the taxonomy will foster consistent language in coding enabling patient, provider, and payer access to the benefits of innovation.
Physical Activity Changes and the Risk of Incident Atrial Fibrillation in Patients With Type 2 Diabetes Mellitus: A Nationwide Longitudinal Follow-up Cohort Study of 1.8 Million Subjects
Authors: Chan Soon Park, Eue-Keun Choi, None Kyung-DoHan, Juhwan Yoo, Hyo-Jeong Ahn, Soonil Kwon, So-Ryoung Lee, Seil Oh, Gregory Y.H. Lip
Journal: Diabetes Care (2022)

OBJECTIVE We investigated the association between alterations in regular physical activity (PA) and the risk of developing AF in patients with type 2 diabetes mellitus (T2DM) and the optimal PA range based on energy expenditure. RESEARCH DESIGN AND METHODS In a nationwide database, subjects who underwent health examinations twice at a 2-year interval between 2009 and 2012 were studied. After 1,815,330 patients with T2DM who did not have a history of AF were identified, they were followed until 2018. Regular PA alterations over time were used to divide individuals into four groups: persistent nonexercisers (n = 1,181,837), new exercisers (n = 242,968), exercise dropouts (n = 225,124), and exercise maintainers (n = 165,401). RESULTS During a mean follow-up period of 5.6 ± 1.3 years, 46,589 cases (2.6%) of new-onset AF occurred. Compared with the persistent nonexerciser group, both the exercise dropout group (adjusted hazard ratio [HR] 0.96, 95% CI 0.94–0.99) and new exerciser group (HR 0.95, 95% CI 0.93–0.98) had lower risks of incident AF. The exercise maintainer group showed the lowest risk (HR 0.91, 95% CI 0.89–0.94). When we stratified patients with T2DM according to energy expenditure, undergoing regular PA with ≥1,500 MET-min/week in new exercisers and ≥1,000 MET-min/week in exercise maintainers was associated with lower risks of incident AF than nonexercisers. CONCLUSIONS In patients with T2DM, starting and maintaining regular PA were both associated with lower risk of incident AF. Optimal PA ranges based on energy expenditure, which were associated with lower risks of incident AF, can be defined.
Changes in Racial Equity Associated With Participation in the Bundled Payments for Care Improvement Advanced Program
Authors: Gmerice Hammond, E. John Orav, Jie Zheng, Arnold M. Epstein, Karen E. Joynt Maddox
Journal: JAMA Network Open (2022)

The Medicare alternative payment models are designed to incentivize cost reduction and quality improvement, but there are no requirements established for evaluating the outcomes of the Medicare populations.To examine whether participation in the Medicare Bundled Payments for Care Improvement Advanced (BPCI-A) program was associated with narrowing or widening of Black and White racial inequities in outcomes and access.Retrospective cohort alternative payment models on equity and quality for disadvantaged populations were studied between April 6, 2021, and August 28, 2022, in US hospitals. Black and White Medicare beneficiaries admitted for any of the 29 inpatient conditions in the BPCI-A program between January 1, 2017, and September 31, 2019, were included.BPCI-A participation implemented in 2018.Ninety-day readmission and mortality, healthy days at home, and proportion of Black patients hospitalized. Segmented regression models were used to examine quarterly changes in slopes for each outcome.The sample included 6 690 336 episodes (6 019 359 White patients, 670 977 Black patients). The population comprised approximately 43% men, 57% women, 17% individuals younger than 65 years, 47% between ages 65 and 80 years, and 36% older than 80 years. Prior to implementation of the BPCI-A program, compared with episodes for White patients, Black patients had higher 90-day readmissions (36.3% vs 29.6%), similar 90-day mortality (12.3% vs 13.3%), and fewer healthy days at home (mean, 68.5 vs 69.5 days). BPCI-A participation was not associated with significant changes in the racial gap in readmissions but was associated with a greater gain in heathy days at home (differences by race, -0.07 days per quarter; 95% CI, -0.12 to -0.01 days per quarter). Among Black patients admitted to BPCI-A hospitals vs controls, healthy days at home increased by 0.09 more days/episode per quarter (95% CI, 0.02-0.17 days/episode per quarter). The proportion of Black patients decreased similarly at BPCI-A and control hospitals.In this cohort study, BPCI-A participation was not associated with improvements in racial inequities in clinical outcomes. Black patients in BPCI-A had a slight gain in healthy days at home; there were no changes in access. The findings of this study suggest that more needs to be done if payment policy reform is going to be part of the efforts to address glaring racial inequities in health care quality and outcomes. These findings support a need for payment policy reform specifically targeting equity-enhancing programs.
A human TRPV1 genetic variant within the channel gating domain regulates pain sensitivity in rodents
Authors: Shufang He, Vanessa O. Zambelli, Pritam Sinharoy, Laura Brabenec, Yang Bian, Freeborn Rwere, Rafaela C.R. Hell, Beatriz Stein Neto, Barbara Hung, Xuan Yu, Meng Zhao, Zhaofei Luo, Chao Wu, Lijun Xu, Katrin J. Svensson, Stacy L. McAllister, Creed M. Stary, Nana-Maria Wagner, Ye Zhang, Eric R. Gross
Journal: Journal of Clinical Investigation (2022)

Pain signals are relayed to the brain via a nociceptive system, and in rare cases, this nociceptive system contains genetic variants that can limit the pain response. Here, we questioned whether a human transient receptor potential vanilloid 1 (TRPV1) missense variant causes a resistance to noxious stimuli and, further, whether we could target this region with a cell-permeable peptide as a pain therapeutic. Initially using a computational approach, we identified a human K710N TRPV1 missense variant in an otherwise highly conserved region of mammalian TRPV1. After generating a TRPV1K710N-knockin mouse using CRISPR/Cas9, we discovered that the K710N variant reduced capsaicin-induced calcium influx in dorsal root ganglion neurons. The TRPV1K710N rodents also had less acute behavioral responses to noxious chemical stimuli and less hypersensitivity to nerve injury, while their response to noxious heat remained intact. Furthermore, blocking this K710 region in WT rodents using a cell-penetrating peptide limited acute behavioral responses to noxious stimuli and returned pain hypersensitivity induced by nerve injury to baseline levels. These findings identify K710 TRPV1 as a discrete site that is crucial for the control of nociception and provide insights into how to leverage rare genetic variants in humans to uncover fresh strategies for developing pain therapeutics.
Whole-body CD8+ T cell visualization before and during cancer immunotherapy: a phase 1/2 trial
Authors: Laura Kist de Ruijter, Pim P. van de Donk, Jahlisa S. Hooiveld-Noeken, Danique Giesen, Sjoerd G. Elias, Marjolijn N. Lub-de Hooge, Sjoukje F. Oosting, Mathilde Jalving, Wim Timens, Adrienne H. Brouwers, Thomas C. Kwee, Jourik A. Gietema, Rudolf S. N. Fehrmann, Bernard M. Fine, Sandra M. Sanabria Bohórquez, Mahesh Yadav, Hartmut Koeppen, Jing Jing, Sebastian Guelman, Mark T. Lin, Michael J. Mamounas, Jeffrey Ryan Eastham, Patrick K. Kimes, Simon P. Williams, Alexander Ungewickell, Derk J. A. de Groot, Elisabeth G. E. de Vries
Journal: Nature Medicine (2022)

Immune checkpoint inhibitors (ICIs), by reinvigorating CD8+ T cell mediated immunity, have revolutionized cancer therapy. Yet, the systemic CD8+ T cell distribution, a potential biomarker of ICI response, remains poorly characterized. We assessed safety, imaging dose and timing, pharmacokinetics and immunogenicity of zirconium-89-labeled, CD8-specific, one-armed antibody positron emission tomography tracer 89ZED88082A in patients with solid tumors before and ~30 days after starting ICI therapy (NCT04029181). No tracer-related side effects occurred. Positron emission tomography imaging with 10 mg antibody revealed 89ZED88082A uptake in normal lymphoid tissues, and tumor lesions across the body varying within and between patients two days after tracer injection (n = 38, median patient maximum standard uptake value (SUVmax) 5.2, IQI 4.0-7.4). Higher SUVmax was associated with mismatch repair deficiency and longer overall survival. Uptake was higher in lesions with stromal/inflamed than desert immunophenotype. Tissue radioactivity was localized to areas with immunohistochemically confirmed CD8 expression. Re-imaging patients on treatment showed no change in average (geometric mean) tumor tracer uptake compared to baseline, but individual lesions showed diverse changes independent of tumor response. The imaging data suggest enormous heterogeneity in CD8+ T cell distribution and pharmacodynamics within and between patients. In conclusion, 89ZED88082A can characterize the complex dynamics of CD8+ T cells in the context of ICIs, and may inform immunotherapeutic treatments.
Association of Adherence to Endocrine Therapy Among Patients With Breast Cancer and Potential Drug-Drug Interactions
Authors: Elie Rassy, Aurélie Bardet, Omar Bougacha, Laurène Gantzer, Béranger Lekens, Suzette Delaloge, Fabrice André, Stefan Michiels, Barbara Pistilli
Journal: JAMA Network Open (2022)

Importance Suboptimal adherence to endocrine therapy (ET) among patients with hormone-receptor–positive breast cancer significantly affects survival outcomes and is associated with higher hospitalization rates and health care costs. Weak adherence to long-term treatments has multiple determinants, including disease characteristics, treatment adverse effects, and patients’ attributes, such as age and comorbidities. Objective To examine whether potential drug-drug interactions (PDDI) with tamoxifen or aromatase inhibitor were associated with adherence to ET in patients with early and advanced breast cancer. Design, Setting, and Participants This cohort study used anonymized health record data of women with breast cancer who received ET in a private observational primary care database. Patients eligible for analysis included women aged 18 years or older who had a reported diagnosis of breast cancer and received ET with tamoxifen or aromatase inhibitor between 1994 and 2021. Data were analyzed 2021. Exposures Adherence to ET during a given year was defined by a medication possession ratio of 80% or greater over 1-year prescription periods. PDDI were categorized into absent, minor (a combination to take into account), moderate (combination requiring precautions for use), major (combination not recommended), and contraindicated according to guidelines in the Claude Bernard Drug Database. Main Outcomes and Measures We used regression models to estimate odds ratios (ORs) and 95% CIs for the associations between adherence and age, baseline comorbidities, PDDI, and adherence to ET during the previous year. Results A total of 10 863 patients who were prescribed ET for breast cancer were eligible for the analysis (age 70 years or older, 3509 patients [32.3%]). In the tamoxifen cohort (3564 patients), PDDI were reported in 497 of 3670 patients (13.5%) at baseline (moderate, 254 patients [51.1%]; major, 227 patients [45.7%]), 2047 of 4831 patients (42.4%) at year 1, 1127 of 2751 patients (41.0%) at year 2, 761 of 1861 patients (40.9%) at year 3, 376 of 1058 patients (35.5%) at year 4, and 201 of 593 patients (33.9%) at year 5. In the aromatase inhibitor cohort (7299 patients), PDDI were reported in 592 of 7437 patients (8.0%) at baseline (moderate in 588 of 592 patients [99.3%]), which reached 2875 of 9031 patients (31.8%) at year 1 and ranged between 31.4% (1802 of 5730 patients in year 2) and 32.8% (791 of 2411 in year 4) throughout the study period. No association between adherence and PDDI was found in the tamoxifen (OR, 0.99; 95% CI, 0.91-1.08) or aromatase inhibitor (OR, 1.05; 95% CI, 0.95-1.15) cohort. Conclusions and Relevance In this cohort of patients with hormone-receptor–positive breast cancer, PDDI with tamoxifen and aromatase inhibitors were not associated with adherence to ET.
Alterations in Functional Connectivity of Thalamus and Primary Somatosensory Cortex in Painful and Painless Diabetic Peripheral Neuropathy
Authors: Suganthiya S. Croosu, Johan Røikjer, Carsten D. Mørch, Niels Ejskjaer, Jens B. Frøkjær, Tine M. Hansen
Journal: Diabetes Care (2022)

In this study we aimed to investigate the functional connectivity of brain regions involved in sensory processing in diabetes with and without painful and painless diabetic peripheral neuropathy (DPN) and the association with peripheral nerve function and pain intensity.In this cross-sectional study we used resting-state functional MRI (fMRI) to investigate functional brain connectivity of 19 individuals with type 1 diabetes and painful DPN, 19 with type 1 diabetes and painless DPN, 18 with type 1 diabetes without DPN, and 20 healthy control subjects. Seed-based connectivity analyses were performed for thalamus, postcentral gyrus, and insula, and the connectivity z scores were correlated with peripheral nerve function measurements and pain scores.Overall, compared with those with painful DPN and healthy control subjects, subjects with type 1 diabetes without DPN showed hyperconnectivity between thalamus and motor areas and between postcentral gyrus and motor areas (all P ≤ 0.029). Poorer peripheral nerve functions and higher pain scores were associated with lower connectivity of the thalamus and postcentral gyrus (all P ≤ 0.043). No connectivity differences were found in insula (all P ≥ 0.071).Higher functional connectivity of thalamus and postcentral gyrus appeared only in diabetes without neuropathic complications. Thalamic/postcentral gyral connectivity measures demonstrated an association with peripheral nerve functions. Based on thalamic connectivity, it was possible to group the phenotypes of type 1 diabetes with painful/painless DPN and type 1 diabetes without DPN. The results of the current study support that fMRI can be used for phenotyping, and with validation, it may contribute to early detection and prevention of neuropathic complications.